Regulation of sodium (Na) absorption in a vital biological function. Derangements of intestinal Na absorption lead to diarrheal diseases, a cause of significant worldwide morbidity and mortality. The gut demonstrates a significant segmental heterogeneity in its mechanisms of Na absorption. The cecum exhibits a high rate of electrogenic Na absorption, neither coupled to anions or nutrients, nor blocked by amiloride. Several lines of evidence suggest that cecal Na absorption may occur through a Na channel significantly modified from the transporter found in distal colon and other tight epithelia, including 1) inhibition of both current and Na absorption by the amiloride analogue phenamil and ii) electrophysiologic demonstration of an apical Na conductance. Through a variety of techniques (Ussing chamber, microelectrodes, patch clamp) we will characterize the macroscopic and microscopic features of cecal Na absorption that account for its distinct transport properties. Proximal colon absorbs Na electroneutrally by Na-H exchange. Several regulators of Na absorption in proximal colon have been identified, including lowered Na in the bathing media, removal of bicarbonate, glucocorticoids and short-chain fatty acids, which have effects on Na transport specific to the proximal colon. We will investigate the intracellular adaptions associated with changes in transepithelial transport by using electrophysiologic techniques (microelectrodes), pH stat and fluorescent dyes. The predominant luminal anions in the colon are short-chain fatty acids (SCFA). Their role in ion transport in vitro has yet to be clearly defined; however, their relation to Na transport and potential role as a significant source for calories ("colonic salvage") are major factors in the function of proximal colon and cecum. We will study SCFA transport in vitro to determine whether absorption is principally transcellular or paracellular, in the acid or ionized form and the relationship to Na transport. The energing models for transport in the cecum and proximal colon provide the opportunity to relate the specific adaptions of these intestinal transporters to their biological function and compare these to other epithelia that exhibit electrogenic or eletro-neutral Na absorption. By characterizing the specific transport processes of cecum and proximal colon, we will achieve a better understanding of the segmental heterogeneity of the gut and gain insight into the colon's handling of fluid and electrolytes, the regional pathophysiology of diarrhea and the role of the colon as a nutritive organ.